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Challenges in Phase III Cancer Clinical Trials

There is a high failure rate of PhIII Cancer trials. One of the main reasons is inadequate or irrelevant information from PhII studies.

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Challenges in Phase III Cancer Clinical Trials

  1. 1. CHALLENGES IN PHASE III CANCER CLINICAL TRIALS NOT ADEQUATE INFORMATION FROM PHASE II Dr. Bhaswat S. Chakraborty Senior Vice President, R&D Cadila Pharmaceuticals Ltd. 1 Presented at the 2nd National Conference (NCIP) on “Emerging Trends in Drug Discovery, Development and Molecular Targets for Cancer Research” at Nirma Univ., Ahmedabad, India, 24-25 January, 2017
  2. 2. CONTENTS  Clinical trial conduct & data  Clinical Development Success & Consequences of Failure  Why examine Failure Reasons  Inadequate Ph II Information  Sample size  Single arm studies  Historical control  Problems with Historical Controls  Patient heterogeity  End point consideration  Remedies  Concluding remarks 2
  3. 3. Investigational Sites Product Management Project Management Drug & Clinical Trial Development Extended Picture IRB Regulatory Documents Relationship Building eMails Partners & Affiliates Meetings CROs Contracts Knowledge Information Safety Communication Resource Management Data Capture Data Management Multidirectional Flow of Activities, Data and Decisions 3
  4. 4. CLINICAL DEVELOPMENT SUCCESS RATE Of the 14 major disease areas, Likelihood of Approval (LOA): Oncology had the lowest (5.1%) Hematology had the highest (26.1%) Sub-indication analysis within Oncology revealed hematological cancers had 2x higher LOA 4 Bio-Industry Analysis June 2017
  5. 5. 5 Consequences of failure can be very dramatic
  6. 6. MOST COMMON REASONS OF PHASE III ONCO TRIAL FAILURE  Lack of efficacy  Lack of Safety  Very rarely Quality  Commercial/Financial/Administrative 6
  7. 7. WHY EXAMINE THE CAUSES OF FAILURE?  Discoverer or Investigator: difficult personal experience given non-clinical data promising  Ethical: Why thousands of patients were exposed to a compound that did not provide a possibility for clinical improvement  Cancer is the 2nd leading cause of mortality in the US  Successful development is relevant not only to professionals but to the general public as well  Potentially huge savings in resources 7
  8. 8. WHAT DOES THE LITERATURE SAY (RE CAUSES OF FAILURE?)  “Negative” findings are typically not published or are published after a substantial delay  Even when published, crucial elements of the study e.g., statistical design are often missing  Original analysis missing, only a retrospectively- defined analysis provided  to have clues or new direction for future research  Gap between +ve & -ve study publications:,  a survey of reported breast cancer Phase 2 studies found that 80% had positive outcome [Perone F et al. (2003). Lancet 4:305-311]  However, can give you some insight 8
  9. 9. BASICS OF PHASE III FAILURE 9 False positive from Ph II: Phase 2,Test is safe & efficacious in targeted population, while the reverse is true Wrong design and implementation of the Ph III, Sample size, patient heterogeneity, wrong end-point etc. … Retzios AD (2009) Bay Clin R&D Services
  10. 10. WRONG INFORMATION FROM PH II  In all areas – Efficacy, Safety, Patient population & sample size, Randomization, Hypotheses, Outcome variables, Levels of α or β, Dose..  Many reasons for inaccuracies all the above areas  Of all phases of CTs, Ph II trials are more likely to give false positives  Any inaccurate information from this phase enhances the possibility of failure in Ph III  Efficacy based Ph II dose ranging study may be required  Toxicity-wise dose ranging study may not make sense 10 Retzios AD (2009) Bay Clin R&D Services
  11. 11. SAMPLE SIZES  Sample sizes are usually smaller (N<300) in Ph II programs 11  d is the tolerance interval of difference between the outcome variable of test and control arms; usually kept large e.g., 20-40%  In actual Ph III studies the “clinical-benefit” oriented endpoits e.g., OS show much smaller margins  Often re-examination and underpowered Ph II studies false +ve
  12. 12. “Investigators consistently make overly-optimistic assumptions regarding treatment benefits when designing RCTs.” Gan HK et al (2012). J Natl Cancer Inst., 104: 590-598 12
  13. 13. SINGLE ARM PH II STUDIES  SA, Two-stage Ph II studies have been very common in Onco  Such oversimple design is based on assumptions:  tumors are unlikely to regress without pharmacological intervention  although certain tumor types show high spontaneous regression rates  % response for the standard treatment (which constitutes a historical control) can be adequately defined  Ph III success depend heavily of how well the historical controls have been defined and  Ph II conclusions in both stages therein are overoptimistic & underpowered 13 Retzios AD (2009) Bay Clin R&D Services
  14. 14. PROBLEMS WITH HISTORICAL CONTROLS  Historical controls are frowned upon and usually discouraged by regulatory guidance outside Oncology  Historical controls are not appropriate comparator for data collected prospectively because of  differences in concomitant treatment  demographics  study entry criteria  time and type of assessments  methodology of measurement  number of other study provisions … 14 Retzios AD (2009) Bay Clin R&D Services
  15. 15. WHY MULTI-ARM, RANDOMIZED DESIGNS WITH ACTIVE OR PLACEBO CONTROL ARE BETTER?  Historical controls are inadequate or non-existent for the newer cytostatic agents  These agents do not result in tumor shrinkage but may have a substantial impact on OS  prohibit tumor growth and metastases  but do not result in substantial tumor size reduction during Ph II studies’ short observation period  Since OS takes a number of years of observation, Ph II RCTs of cytostatic agents normally utilize disease progression endpoints 15
  16. 16. PATIENT HETEROGENEITY  Patient heterogeneity in small sized Ph II trials remains a major challenge  If relevant covariates (e.g., patient molecular phenotype) are not balanced, a +ve or -ve difference from control may reflect imbalance in these covariates  study: weekly docetaxel + trastuzumab vs weekly paclitaxel plus trastuzumab in NSCLC  randomized patients also stratified on HER-2 protein expression (trastuzumab targets the HER-2/neu receptor)  The study did not reveal any advantages for these treatments, but the approach was valid 16
  17. 17. RANDOMIZED DISCONTINUATION DESIGNS  Two stage trial  all patients are treated with the test  patients with stable disease are then randomized to either the test or control (placebo or current treatment)  disease progression is assessed  stage 1 ceases when calculated stage 2 randomized sample size is achieved  Essentially, these are enriched designs  The resulting sample is more homogeneous  reduces variance and increases power of thestudy  Problems: the drug effect has been amplified & blinding in stage 2 may be difficult if the active treatment has a certain toxic profile 17
  18. 18. END-POINT CONSIDERATIONS  In Ph III, the primary endpoint must be well-defined and show accepted clinical benefit (often OS)  In Ph II, surrogate endpoints (usually pharmacodynamic or disease progression) may be OK  but not correspond directly to measurable clinical benefit  Whereas provides strong evidence of pharmacological activity  Ph II endpoints are usually speedier and less costly  usually PFS, objective tumor response, TTP  RECIST or WHO criteria tumor response correlates well with OS for solid tumors &cytotoxic compounds tumor response does not work for melanoma and renal cell cancer and for cytostatic agents 18
  19. 19. PROBLEMS (& MERITS) OF TTP & PFS  In many cases Ph II PFS and TTP correlate with Ph III OS outcome  Works well for cytostatic anti-cancers  Problems with PFS and TTP  highly influenced by frequency of assessments  Disease progression in period of observation (few mo to a yr) is highly variable among patients  Sometimes it is difficult to assign lack of progression to drug’s pharmacological action  both PFS and TTP are very susceptible to investigator bias  cannot be used in non-randomized, multi-stage trials 19
  20. 20. FAULTY CONDUCT OF PH II STUDIES  Many Ph II studies are inadequately conducted  Numerous protocol violations and deviations  protocol violations noted in ≥ 20% of enrolled subjects make the study unreliable  GCP violations are rampant across the globe  Data integrity issues  Sites and investigators are not appropriately trained  Go/no go decisions are often strongly affected by the desire to succeed at any cost  PoCs are often Proof of Cleverness  the therapeutic effect is overestimated & consequently, the pivotal studies fail to achieve the desired endpoint 20
  21. 21. COMPREHENSIVE FAILURE TRIGGERS Drivers of Failure Examples Inadequate Basic Science •Beneficial effects in animal models not reproduced in humans •Poor understanding of target disease biology Flawed Study Design •Patient population definition changed from phase –II to phase –III •Phase –II surrogate endpoint not confirmed by Phase-III clinical outcomes Suboptimal dose selection •Inadequate dose finding in Phase-II •Poor therapeutic indices 21 Parexel
  22. 22. COMPREHENSIVE FAILURE TRIGGERS.. Drivers of Failure Examples Flawed data collection and analysis • Phase-II false positive effects were not replicated in Phase-III •Overoptimistic assumptions on variability and treatment difference •Missing data; attrition bias; rater bias •Wrong statistical tests; other statistical issues Problems with study operations •Data integrity issues; GCP violations •Recruitment, dropouts, noncompliance and protocol •Missing data; unintentional unblinding Other •Insufficient landscape assessment of current standard of care and precedents. 22
  23. 23. WELL DESIGNED PH II RCT 23 Belani, Chakraborty, Modi & Khamar (2016) Annals of Oncology
  24. 24. FRAMEWORK Right Target •Strong link between target and disease •Differentiated efficacy •Available and predictive biomarkers Right Tissue •Adequate bioavailability and tissue exposure •Definition of PD biomarkers •Clear understanding of pre-clinical and clinical PK/PD •Understanding of drug-drug interactions 24 Optimize a rational and effective the entire Clinical Development process
  25. 25. ASTRAZENECA’S THE 5R FRAMEWORK.. 25 •Differentiated and clear safety margins •Understanding of secondary pharmacology risks •Understanding of reactive metabolites, Genotoxicity, dr-dr interactions •Understanding of target liability Right Patients •Identification of the most responsive patient population •Definition of risk-benefit for given population Right Commercial Potential •Differentiated value proposition versus standard of care •Focus on market access, payer and provider •Personalized healthcare strategy, including diagnostic and biomarkers Right Safety
  26. 26. OTHER AREAS OF REDUCING PHASE III FAILURE RISKS  Replacement of the current gold standard, the randomized controlled trial, with real-world evidence  Wearable devices that collect real-time data  Adaptive licensing  Next-generation sequencing and improved understanding of the genetic basis of disease  Basket/master protocols  Phase III failures cannot be eliminated, can only be reduced 26
  27. 27. CONCLUDING REMARKS  Well designed, properly conducted Ph II cancer RCTs can provide a sound basis of go/no go for Ph III  Careful evaluation of historical data, correct design and sample size, appropriate end-point are some of the keys  A good trade-off between completing Ph II in time and obtaining accurate information is required  Planning at Ph II level should include a clear idea as to what needs to be achieved in the pivotal Ph III  both in terms of the population to be treated & therapeutic advantage to be sought  A comprehensive clinical development & data integrity plan helps  Also awareness of the competitive environment and the construction of a target label ae required 27
  28. 28. THANK YOU VERY MUCH 28